Modern advances in medicine have caused an increase in the average life span of individuals. However, in today's era of an aging population, the molecular mechanisms of the aging process remain poorly understood. The recent identification of genes in Saccharomyces cerevisiae, Caenorhabditis elegans, and humans that effect the rate at which these organisms age has opened the door to the molecular and genetic characterization of the aging process. This research proposal addresses the aging process in S. cerevisiae by genetic and biochemical approaches. Specifically, these studies will examine the role and mechanism by which the silent information regulator protein, Sir2p, regulates S. cerevisiae life span. The SIR2 gene is involved in a number of chromosomal processes. Recent findings have suggested that Sir2p contains ADP-ribosyltransferase activity. This proposal will address the function of the putative Sir2p ADP-ribosyltransferase domain with respect to chromosomal dynamics and the regulation of aging. Because Sir2-like proteins are conserved in higher eukaryotes, these studies should provide insights into the role of Sir2-like proteins in mammalian species and possibly the aging process in mammals as well.